人血清蛋白—无机纳米复合材料用于金属抗癌的运输
发布时间：2018-12-12 13:10
【摘要】：每年全球有上千万的癌症新增患者,癌症已经严重威胁着人类的生命健康,在药物治疗中,金属抗癌药物有着举足轻重的作用,顺铂、卡铂、奥沙利铂、三氧化二砷等被广泛用于临床治疗,其他一些金属药物比如,NAMI-A、KP1019等钌类抗癌药物和金类抗癌药物等进入临床评估。但在临床治疗中表现出的毒副作用、耐药性以及小分子药物在体内循环时间短等问题极大限制了其使用。本论文主要研究内容有(1)以磷酸钙纳米颗粒和人血清白蛋白为载体运输四价铂化合物,使得该体系能够在酸性及还原性环境中响应释放出顺铂药物；(2)以人血清白蛋白修饰的上转换纳米颗粒为载体运输光敏性的多吡啶钌化合物,该体系具有双重荧光特性,用于细胞成像,而且能够通过光照控制释放抗癌活性药物；(3)合成轴向为阿司匹林的四价铂化合物,该化合物能够在细胞内还原释放出顺铂和阿司匹林,显著增加了抗肿瘤活性,而且通过在四价铂轴向另一端接上胆固醇分子,使得阿司匹林-铂化合物疏水性增加,能够有效被高分子纳米颗粒负载。第一章主要是对金属抗癌药物及纳米运输体系的综述,主要涉及铂类、钌类抗癌药物的发展、挑战及其抗癌作用机理,铂类、钌类药物的纳米运输体系的发展及抗癌作用机理,人血清白蛋白简介及其用于药物运输的发展和体内抗癌作用机理。第二章设计合成了一种四价铂-HSA/磷酸钙载药体系,通过共价键把四价铂化合物结合到HSA上,再通过共沉淀方法制备出Pt(IV)-HSA-CaP体系,该载药体系是一种生物兼容性好,能够对PH及氧化还原环境响应的纳米运输体系,Pt-HSA/CaP在细胞外液稳定,当颗粒被细胞摄入后,在溶酶体或包涵体酸性环境中,磷酸钙降解,释放出Pt-HSA药物,四价铂化合物在细胞内还原剂(AsA)存在下,还原释放出具有抗癌活性的二价铂。从实验结果可以得到,Pt-HSA只有在还原剂AsA存在下才能和DNA反应,而磷酸钙载体保护四价铂化合物不会提前被体液中还原剂还原,所以该体系是一种能有效控制药物释放的运输体系,从细胞毒性实验结果可以看到,Pt-HSA/CaP体系相比于顺铂,能够更有效的抑制癌细胞的生长,而对正常细胞毒性较弱,而且跟顺铂、Pt-HSA相比,该体系也表现出不同的细胞周期阻滞,说明在Pt-HSA/CaP中的Pt(Ⅳ)在细胞内有不同细胞响应。在Pt-HSA/CaP体系中,制备材料的试剂都是生物兼容性的,而且制备条件温和,对磷酸钙颗粒中的蛋白质性质影响较小,加上该体系有很高的蛋白质负载量,所以该体系有望用于蛋白质药物运输。第三章合成三种多吡啶钌化合物,通过比较其光敏性及光毒性,选出[Ru(bpy)2(6,6'-dimethyl-2,2'-bipyridine)]Cl2 (Ru-1)化合物作为光敏性钌药物用于纳米药物运输,通过多空硅、PAA、HSA表面修饰UCNPs,研究不同表面修饰对颗粒稳定性及多吡啶钌化合物负载效率的影响,得到HSA修饰的UCNPs具有优异的稳定性和负载效率,通过HSA包覆使得该纳米颗粒具有很好的生物相容性、水分散性和稳定性,而且通过HSA表面修饰UCNPs获得一种具有双重荧光的纳米载体,该载体在980nm光激发下,内核UCNPs (NaYF4:20 mol% Yb,0.5mo1%Tm)会产生蓝色荧光,而在450nm光激发下,HSA层产生绿色荧光,这双重荧光特性使得该纳米载体能够有效用于生物成像,而且提供更多的激发波长和发射波长选择,载体的细胞摄取能够同时通过上转换荧光和绿色荧光看到,通过负载一种光敏性钌化合物Ru-1到载体中,形成Ru-HSA-UCNPs纳米颗粒,该纳米颗粒具有光诱导的细胞毒性,在黑暗条件下,Ru-HSA-UCNPs只有很低的细胞生长抑制效果,但光激发后细胞毒性显著增加。进一步分析Ru-1化合物和DNA的反应,实验结果表明,Ru-1化合物和DNA有很低的反应活性,但被光激活后,Ru-1化合物转变为具有高反应活性的化合物,能够和DNA反应,而且和DNA反应速率比顺铂快。这种光激活特性使得Ru-HSA-UCNPs有希望用于在肿瘤部位定点控制释放活性抗肿瘤基团。第四章合成了一种新型四价铂化合物,其轴向是一个阿司匹林分子,该化合物被细胞摄取后,在细胞内被还原释放出顺铂和阿司匹林,显著增加了抗肿瘤活性；为了能够运用高分子载体有效运输阿司匹林-铂白化合物,设计合成在其轴向另一端为胆固醇分子的阿司匹林-铂化合物,使其疏水性增加,能够被PEG-PLGA等高分子纳米颗粒的疏水性内核高效负载。
[Abstract]:Every year, there are tens of millions of newly-added cancer patients in the world, and the cancer has seriously threatened the health of human life. In the treatment of drugs, the metal anti-cancer drugs play a very important role, such as cisplatin, carboplatin, oxaliplatin, arsenic trioxide and the like, and are widely used for clinical treatment. Other metal drugs, such as NMI-A, KP1019, and other anti-cancer drugs and gold-based anti-cancer drugs, will enter the clinical evaluation. but the problems of toxic and side effects, drug resistance and short molecular medicine in the in-vivo circulation time and the like in the clinical treatment are greatly limited. The main contents of this thesis are as follows: (1) the tetravalent platinum compound is transported with calcium phosphate nanoparticles and human serum albumin as a carrier, so that the system can respond to the release of the cisplatin medicament in an acid and a reducing environment; (2) the light-sensitive multiferroic compound is transported by the upconversion nanoparticles modified by human serum albumin as a carrier, the system has double fluorescence characteristics, is used for cell imaging, and can release the anti-cancer active drug through illumination control; (3) synthesizing a tetravalent platinum compound with an axial direction of aspirin, capable of reducing the release of cisplatin and aspirin in the cells, remarkably increasing the anti-tumor activity, and connecting the cholesterol molecules at the other end of the tetravalent platinum, so that the hydrophobic property of the aspirin-platinum compound is increased, and the high-molecular nano-particle load can be effectively absorbed. The first chapter is the review of the metal anti-cancer drug and the nano-transportation system, which mainly deals with the development, challenge and the mechanism of anti-cancer action, the development of the nano-transport system of platinum and the anti-cancer drugs and the mechanism of the anti-cancer action. The introduction of human serum albumin and its application in the development of drug transport and the mechanism of anti-cancer in vivo. in that second chap, a tetravalent platinum-HSA/ calcium phosphate drug delivery system is designed, the tetravalent platinum compound is bound to the HSA by a covalent bond, a Pt (IV)-HSA-CaP system is prepared by a co-precipitation method, The nano-transport system capable of responding to the PH and the oxidation-reduction environment, the Pt-HSA/ CaP is stable in the extracellular fluid, and the Pt-HSA drug and the tetravalent platinum compound are released in the presence of an internal reducing agent (AsA) in the cell when the particles are taken up by the cells, reducing the release of the divalent platinum with anticancer activity. from the experimental results, the Pt-HSA can only react with the DNA in the presence of the reducing agent AsA, and the calcium phosphate carrier protects the tetravalent platinum compound from being reduced in advance by the reducing agent in the body fluid, so the system is a transport system capable of effectively controlling the release of the drug, Compared with the cisplatin, the Pt-HSA/ CaP system can effectively inhibit the growth of the cancer cells compared with the cisplatin-HSA/ CaP system, and the system also shows different cell cycle blocks compared with the cisplatin and the Pt-HSA, The Pt (IV) in the Pt-HSA/ CaP has different cell responses in the cells. In the Pt-HSA/ CaP system, the reagents for preparing the materials are biocompatible, and the preparation conditions are mild, the effect of the protein in the calcium phosphate particles is small, and the system has high protein loading, so the system is expected to be used for protein drug transportation. In the third chapter, three kinds of multiferroic compounds were synthesized. By comparing their photosensitivity and phototoxicity,[Ru (bpy) 2 (6, 6 '-dimetyl-2,2'-biyridine)] Cl2 (Ru-1) compound was used as a photosensitizing agent for the transport of nano-drugs, and the UCNPs were modified by the surface modification of multi-space silicon, PAA and HSA. The effect of different surface modification on the particle stability and the loading efficiency of the multiferrosilicon compound is studied, the obtained HSA-modified UCNPs has excellent stability and loading efficiency, and the nano-particles have good biocompatibility, water dispersibility and stability through the HSA coating, and a nano carrier with double fluorescence is obtained through the HSA surface modification UCNPs, and under the excitation of 980nm light, the core UCNPs (NaYF4: 20 mol% Yb, 0. 5mo1% Tm) can generate blue fluorescence, and the HSA layer generates green fluorescence under the excitation of 450nm light, the dual fluorescence properties enable the nano-carrier to be effectively used for biological imaging and to provide more excitation wavelengths and emission wavelength selection, the cell uptake of the vector can be seen simultaneously by the up-conversion of the fluorescence and the green fluorescence, by loading a photosensitive compound ru-1 into the carrier, The Ru-HSA-UCNPs nanoparticles are formed, and the nano-particles have light-induced cytotoxicity. Under the dark condition, the Ru-HSA-UCNPs only have very low cell growth inhibition effect, but the cytotoxicity of the after-excitation is obviously increased. The reaction of Ru-1 compound and DNA was further analyzed. The results showed that the Ru-1 compound and the DNA had a very low reactivity, but after the photoactivation, the Ru-1 compound was transformed into a compound with a high reactivity, and it was able to react with the DNA, and the reaction rate of the DNA and the DNA was faster than that of the cisplatin. This light-activation characteristic enables the Ru-HSA-UCNPs to be used to control the release of the active anti-tumor group at the site of the tumor. In the fourth chapter, a novel tetravalent platinum compound is synthesized, the axial direction of which is an aspirin molecule, after the compound is taken up by the cells, the cisplatin and the aspirin are released in the cells, and the anti-tumor activity is obviously increased; in ord to be capable of effectively transport aspirin-platinum white compound by using a high-molecular carrier, an aspirin-platinum compound is designed and synthesized at the other end of the aspirin-platinum compound, so that the hydrophobicity of the aspirin-platinum compound is increased, and the high-molecular nano-particle hydrophobic core of the PEG-PLGA can be loaded with high efficiency.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5
本文编号：2374622
[Abstract]:Every year, there are tens of millions of newly-added cancer patients in the world, and the cancer has seriously threatened the health of human life. In the treatment of drugs, the metal anti-cancer drugs play a very important role, such as cisplatin, carboplatin, oxaliplatin, arsenic trioxide and the like, and are widely used for clinical treatment. Other metal drugs, such as NMI-A, KP1019, and other anti-cancer drugs and gold-based anti-cancer drugs, will enter the clinical evaluation. but the problems of toxic and side effects, drug resistance and short molecular medicine in the in-vivo circulation time and the like in the clinical treatment are greatly limited. The main contents of this thesis are as follows: (1) the tetravalent platinum compound is transported with calcium phosphate nanoparticles and human serum albumin as a carrier, so that the system can respond to the release of the cisplatin medicament in an acid and a reducing environment; (2) the light-sensitive multiferroic compound is transported by the upconversion nanoparticles modified by human serum albumin as a carrier, the system has double fluorescence characteristics, is used for cell imaging, and can release the anti-cancer active drug through illumination control; (3) synthesizing a tetravalent platinum compound with an axial direction of aspirin, capable of reducing the release of cisplatin and aspirin in the cells, remarkably increasing the anti-tumor activity, and connecting the cholesterol molecules at the other end of the tetravalent platinum, so that the hydrophobic property of the aspirin-platinum compound is increased, and the high-molecular nano-particle load can be effectively absorbed. The first chapter is the review of the metal anti-cancer drug and the nano-transportation system, which mainly deals with the development, challenge and the mechanism of anti-cancer action, the development of the nano-transport system of platinum and the anti-cancer drugs and the mechanism of the anti-cancer action. The introduction of human serum albumin and its application in the development of drug transport and the mechanism of anti-cancer in vivo. in that second chap, a tetravalent platinum-HSA/ calcium phosphate drug delivery system is designed, the tetravalent platinum compound is bound to the HSA by a covalent bond, a Pt (IV)-HSA-CaP system is prepared by a co-precipitation method, The nano-transport system capable of responding to the PH and the oxidation-reduction environment, the Pt-HSA/ CaP is stable in the extracellular fluid, and the Pt-HSA drug and the tetravalent platinum compound are released in the presence of an internal reducing agent (AsA) in the cell when the particles are taken up by the cells, reducing the release of the divalent platinum with anticancer activity. from the experimental results, the Pt-HSA can only react with the DNA in the presence of the reducing agent AsA, and the calcium phosphate carrier protects the tetravalent platinum compound from being reduced in advance by the reducing agent in the body fluid, so the system is a transport system capable of effectively controlling the release of the drug, Compared with the cisplatin, the Pt-HSA/ CaP system can effectively inhibit the growth of the cancer cells compared with the cisplatin-HSA/ CaP system, and the system also shows different cell cycle blocks compared with the cisplatin and the Pt-HSA, The Pt (IV) in the Pt-HSA/ CaP has different cell responses in the cells. In the Pt-HSA/ CaP system, the reagents for preparing the materials are biocompatible, and the preparation conditions are mild, the effect of the protein in the calcium phosphate particles is small, and the system has high protein loading, so the system is expected to be used for protein drug transportation. In the third chapter, three kinds of multiferroic compounds were synthesized. By comparing their photosensitivity and phototoxicity,[Ru (bpy) 2 (6, 6 '-dimetyl-2,2'-biyridine)] Cl2 (Ru-1) compound was used as a photosensitizing agent for the transport of nano-drugs, and the UCNPs were modified by the surface modification of multi-space silicon, PAA and HSA. The effect of different surface modification on the particle stability and the loading efficiency of the multiferrosilicon compound is studied, the obtained HSA-modified UCNPs has excellent stability and loading efficiency, and the nano-particles have good biocompatibility, water dispersibility and stability through the HSA coating, and a nano carrier with double fluorescence is obtained through the HSA surface modification UCNPs, and under the excitation of 980nm light, the core UCNPs (NaYF4: 20 mol% Yb, 0. 5mo1% Tm) can generate blue fluorescence, and the HSA layer generates green fluorescence under the excitation of 450nm light, the dual fluorescence properties enable the nano-carrier to be effectively used for biological imaging and to provide more excitation wavelengths and emission wavelength selection, the cell uptake of the vector can be seen simultaneously by the up-conversion of the fluorescence and the green fluorescence, by loading a photosensitive compound ru-1 into the carrier, The Ru-HSA-UCNPs nanoparticles are formed, and the nano-particles have light-induced cytotoxicity. Under the dark condition, the Ru-HSA-UCNPs only have very low cell growth inhibition effect, but the cytotoxicity of the after-excitation is obviously increased. The reaction of Ru-1 compound and DNA was further analyzed. The results showed that the Ru-1 compound and the DNA had a very low reactivity, but after the photoactivation, the Ru-1 compound was transformed into a compound with a high reactivity, and it was able to react with the DNA, and the reaction rate of the DNA and the DNA was faster than that of the cisplatin. This light-activation characteristic enables the Ru-HSA-UCNPs to be used to control the release of the active anti-tumor group at the site of the tumor. In the fourth chapter, a novel tetravalent platinum compound is synthesized, the axial direction of which is an aspirin molecule, after the compound is taken up by the cells, the cisplatin and the aspirin are released in the cells, and the anti-tumor activity is obviously increased; in ord to be capable of effectively transport aspirin-platinum white compound by using a high-molecular carrier, an aspirin-platinum compound is designed and synthesized at the other end of the aspirin-platinum compound, so that the hydrophobicity of the aspirin-platinum compound is increased, and the high-molecular nano-particle hydrophobic core of the PEG-PLGA can be loaded with high efficiency.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5
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